This application is a U.S. National Phase Application of PCT/CA97/00007, filed on Jan. 8, 1997, which claims priority to Canadian Applications 2,167,044, filed on Jan. 11, 1996, and 2,193,921, filed on Dec. 24, 1996.
This invention relates to the oral administration of forms of hyaluronic acid (for example hyaluronan (hyaluronic acid) and pharmaceutically acceptable salts thereof such as sodium hyaluronate), and orally administrable dosage forms containing forms of hyaluronic acid, for the prevention and/or treatment of diseases and/or conditions such as the prevention of restenosis and the treatment of an infarct (heart attack) or a stroke. The oral administration and the orally administered dosage forms may also include therapeutic agents and/or medicines which may be administered orally for the treatment and/or prevention of the diseases and/or conditions with the forms of hyaluronic acid (hyaluronan).
In International Publication W095/26193 (Application PCT/CA94/00188), hyaluronic acid and/or pharmaceutically acceptable salts thereof are administered to prevent restenosis of the arterial walls when the artery walls are traumatized by for example balloon angioplasty.
Generally a newborn""s arteries each consist of the outer adventitia and inner intima. The inner surface of the intima presents an elastic lamina. As the newborn grows into an adult human, a neointima (made of migrating smooth muscle cells, leucocytes (macrophages) and fat deposited in the leucocytes (macrophages)(in foamy cells)), develops radially inwardly of the intima, thus narrowing or constricting the opening in the artery (stenosis). This narrowing or constriction reduces blood flow. The development of the neointima depends on the human""s diet, physical conditioning and physical and genetic make-up.
In some people, the size of the neointima has substantially constricted the blood flow through the artery, jeopardizing the human""s life. In an attempt to reduce/alleviate the effects of the size of the neointima and its affects on the human, balloon angioplasty is performed reducing the radial inward extent of the neointima. However in a substantial number of the humans receiving this procedure, restenosis of the artery occurs by migration of the smooth muscle cells to, and concentration of leucocytes carrying fat deposits at, the place of the balloon angioplasty thus increasing the radial inward extent of the neointima.
The teachings of publication WO95/26193 provide a procedure for preventing restenosis using forms of hyaluronic acid administered before, during and/or after the balloon angioplasty procedure. Suitable amounts may be administered intravenously, by injection, or subcutaneously. The form of hyaluronic acid preferably had a molecular weight of less than 750,000 daltons and in one embodiment a concentration of about 2% by weight in sterile water. Effective amounts of the form of hyaluronic acid provided in each dosage administered were from about 10 mg/70 kg human to in excess of 3000 mg/70 kg person, prior to, during and/or after the angioplasty procedure. The oral route was not given as one of the preferred routes. The reason is that persons skilled in the art generally believe that oral administration of the form of hyaluronic acid will not at least for small amounts pass the form of hyaluronic acid into the blood system from the stomach. Such persons believe that a substantial portion of any orally administered form of hyaluronan will be digested, degraded or disassociated into its smaller sugar components in the stomach by the stomach acid before a substantial amount of the form of hyaluronan (greater than K (1000) daltons) can enter the blood system. Thus according to the beliefs of pesons skilled in the art, very large dosage amounts of the form of hyaluronan would have to be administered orally for oral delivery to be effective, and even then consider it unlikely to escape the stomach as intact high molecular weight HA.
Publication WO91/04058 (Application PCT/CA90/00306) teaches the use of a minimum amount of 10 mg/70 kg person of a form of hyaluronan up to in excess of 3000 mg/70 kg person to transport medicines and/or therapeutic agents to the site in the human body in need of the treatment, with preferred amounts exceeding 50 mg/70 kg person to about 350 mg/70 kg person [Page 26, lines 32-371]. At page 18, reference is made to the proposed routes of administration. One of the routes proposed to be used is by oral administration [Page 18, line 5]. However not one of the specific examples in the document, provides specifics using the oral route. At that time oral administration was thought not to be that efficient. While the oral route may have been proposed, persons skilled in the art would believe much of the administered form of hyaluronan would not pass intact into the blood stream. Therefore persons skilled in the art would prefer the other routes for example, intravenous and direct injection when employing the teachings of the document.
Hence Applicants herein believe that oral administration of forms of hyaluronan would not be preferred by persons skilled in the art or in fact be used because to their minds there are better alternate routes. For example the routes of administration of the hyaluronic acid as taught by U.S. Pat. No. 4,808,576 are intramuscular, intravenous, subcutaneous and topical (Column 3, lines 17-18). No teaching of oral administration of hyaluronic acid is proposed as it was believed at that time (even to the present date) that oral administration would not be as good a route.
Thus Applicants believe that the preferred routes of administration to persons skilled in the art are systemic (intravenous, direct injection), subcutaneous and most recently topical. However systemic administration requires hospital or medical clinic time for administrationxe2x80x94a costly procedure even under xe2x80x9cout-patientxe2x80x9d treatment conditions. If the patient in the hospital were to be treated by intravenous administration or by subcutaneous injection over for example 3-5 days, the costs can be substantial. For many conditions, topical treatment is not appropriate.
It is therefore an object of this invention to provide for the prevention and/or treatment of diseases and/or conditions by the oral administration of forms of hyaluronic acid (hyaluronan).
It is a still further object of the invention to provide orally administrable dosages containing forms of hyaluronan which allow the orally administrable form of intact hyaluronan in the stomach prior to passage into the blood stream, in a biologically active form (35,000 daltons to 2,000,000 daltons) determined by the Dextran Standard. (The conversion factor from the newer Dextran Standard to the older Protein Standard on which earlier filed applications were based, is in the order of about 3.3. The molecular weight determined under the newer Dextran Standard must be divided by 3.3 to determine the molecular weight under the older Protein Standard. Thus, the above molecular weights would be between about 11,000 daltons to about 600,000 K. daltons.)
It is a further object of the invention to provide dosages containing forms of hyaluronan for oral administration.
Further and other objects of the invention will be realized by those skilled in the art from the following summary of the invention and detailed discussion of embodiment thereof.
In the development of this invention, the inventors have discovered:
(a) that unexpectedly, hyaluronan when administered orally can be effective to treat and/or prevent a condition and/or disease of a human, such as prevent restenosis;
(b) that unexpectedly xe2x80x9cmorexe2x80x9d hyaluronan is not necessarily better and that unexpectedly xe2x80x9clessxe2x80x9d hyaluronan may be better (for example dosage amounts between about 3 mg/kg of body weight of a human to about 100 mg/kg of a human of a form of hyaluronan and preferably between about between 3 mg/kg to about 30 mg/kg of a human and more preferably between about 3 mg/kg to about 10 mg/kg for example to prevent restenosis, is preferred (the effect of the administered dosage amounts of the form of hyaluronan thereby beingxe2x80x9cphasicxe2x80x9d)); and
(c) that unexpected molecular weight distributions of the form of hyaluronan, ranging from 30,000 to greater than 70,000 daltons (determined by the well known Protein Standard), and in the human between 30,000 to 2,000,000 daltons using the Dextran Standard (which is believed to be more accurate) are the molecular weights of the form of hyaluronan that appear in plasma after administered orally (for example comprising a solution of 2% sodium hyaluronate by weight in sterile water) preventing minimal degradation by the human body when given orally, compared to subcutaneous or intravenous administration. [Once again, conversion of the molecular weight determined by the Dextran Standard must be divided by the conversion factor which factor is in the order of about 3.3. Thus the molecular weights of 30,000 to 2,000,000 daltons using the Dextran Standard correspond from about 9,000 daltons to about 600,000 daltons in the older Protein Standard.]
Therefore new dosages for administration to humans, each dosage containing forms of hyaluronan which the human body can easily use (by delivering the form of hyaluronan directly from the stomach into the blood stream) may comprise in suitable form (preferably liquid form) for oral administration in a suitable excipient (for example sterile water), at least one of the following:
(i) between about 3 mg of the form of hyaluronan/kg to about 100 mg of the form of hyaluronan/kg of body weight of the human taking the oral dose form, in the oral dosage form (preferably between about 3 mg/kg and about 30 mg/kg of the human of the form of hyaluron and more preferably the amount of the form of hyaluronan is between about 3 mg/kg to about 10 mg/kg of the body weight of the human taking the oral dosage) and
(ii) the form of hyaluronan in the orally administrable dosage form having a mean average molecular weight distribution in the range selected from the following group of ranges,
(a) between about 30,000 to 2,000,000 daltons is detected by Dextran Standards (which corresponds to between about 9,000 daltons and about 600,000 daltons delivered by the Protein Standard using the conversion factor of about 3.3), and
(b) about 30,000 to greater than 70,000 daltons as detected by the Protein Standards.
(for example as a 2% by weight solution of hyaluronan in sterile water).
Therefore new methods of treatment and/or prevention of a disease and/or condition, for example prevention of restenosis, is provided comprising orally administering an effective amount of an orally administrable pharmaceutical dosage form comprising the form of hyaluronan for such period of time as required (including any maintenance therapy). For example for the prevention of restenosis the oral administration of a dosage according to the invention may take place before,during and/or after balloon angioplasty, The dosage is constituted according to the above new dosages. Thereafter the oral administration of the oral dosages takes place as needed (for example to prevent restenosis after balloon angioplasty, oral administration may take place for a period of 3-5 days after the balloon angioplasty procedure as maintenance therapy). This administration can be carried out by patients at home simply following their doctors"" instructions by taking their oral dosages.
The form of hyaluronan may comprise hyaluronic acid and/or pharmaceutically acceptable salts thereof, for example, sodium hyaluronate.
Where the form of hyaluronic acid used in the oral dosage form does not have a molecular weight in the ranges specified above in subparagraph (ii) (a), (b) or (c), the form of hyaluronan preferably has a molecular weight less than 750,000 daltons (Protein Standard), for example 400,000 daltons (Protein Standard) in the amounts specified in subparagraph (i) above.
One form of hyaluronic acid and/or pharmaceutically acceptable salts thereof suitable for use is a fraction supplied by Hyal Pharmaceutical Corporation (Applicant herein). One such amount is a 15 ml vial of Sodium hyaluronate 20 mg/ml (300 mg/vialxe2x80x94Lot 2F3). The sodium hyaluronate fraction is a 2% solution with a mean average molecular weight distribution of about 225,000 daltons (Protein Standard). The amount also contains water q.s. which is triple distilled and sterile in accordance with the U.S.P. for injection formulations. The vials of hyaluronic acid and/or pharmaceutically acceptable salts thereof may be carried in a Type 1 borosilicate glass vial closed by a butyl stopper which does not react with the contents of the vial.
Many forms of hyaluronan may be suitable for use herein. Particularly, molecular weights of forms of hyaluronan between about 150,000 daltons (Protein Standard) and about 750,000 daltons (Protein Standard) in sterile water prepared having a viscosity for intravenous administration are suitable.
One specific form of pharmaceutical grade is a 1% sterile sodium hyaluronate solution (50 ml vials) provided by Hyal Pharmaceutical Corporation which has the following characteristics:
This pharmaceutical grade 1% sterile solution of hyaluronan may be made from granules/powder having the following characteristics:
A topical grade of hyaluronan (which may be sterilized) may, in certain circumstances be suitable and may be made from the following granules/powder which have the following characteristics:
This topical grade may then be sterilized.
Other forms may be suitable such as one form of hyaluronic acid and/or pharmaceutically acceptable salts thereof (for example, sodium salt) may be an amount also supplied by Hyal Pharmaceutical Corporation. One such amount is a 15 ml vial of Sodium hyaluronate 20 mg/ml (300 mg/vialxe2x80x94Lot 2F3). The sodium hyaluronate fraction is a 2% solution with a mean average molecular weight of about 225,000 (Protein Standard). The amount also contains water q.s. which is triple distilled and sterile in accordance with the U.S.P. for injection formulations. The vials of hyaluronic acid and/or salts thereof may be carried in a Type 1 borosilicate glass vial closed by a butyl stopper which does not react with contents of the vial.
The amount of hyaluronic acid and/or salts thereof (for example sodium salt) may comprise hyaluronic acid and/or salts thereof having the following characteristics:
a purified, substantially pyrogen-free fraction of hyaluronic acid obtained from a natural source having at least one characteristic selected from the group consisting of the following:
i) a molecular weight within the range of 150,000-225,000 (Protein Standard);
ii) less than about 1.25% sulphated mucopolysaccharides on a total weight basis;
iii) less than about 0.6% protein on a total weight basis;
iv) less than about 150 ppm iron on a total weight basis;
v) less than about 15 ppm lead on a total weight basis;
vi) less than 0.0025% glucosamine;
vii) less than 0.025% glucuronic acid;
viii) less than 0.025% N-acetylglucosamine;
ix) less than 0.0025% amino acids;
x) a UV extinction coefficient at 257 nm of less than about 0.275;
xi) a UV extinction coefficient at 280 nm of less than about 0.25; and,
xii) a pH within the range of 7.3-7.9. Preferably, the hyaluronic acid is mixed with water and the fraction of hyaluronic acid fraction has a mean average molecular weight within the range of 150,000-225,000 (Protein Standard).
Preferably this amount of hyaluronic acid comprises at least one characteristic selected from the group consisting of the following characteristics:
i) less than about 1% sulphated mucopolysaccharides on a total weight basis;
ii) less than about 0.4% protein on a total weight basis;
iii) less than about 100 ppm iron on a total weight basis;
iv) less than about 10 ppm lead on a total weight basis;
v) less than 0.00166% glucosamine;
vi) less than 0.0166% glucuronic acid;
vii) less than 0.016% N-acetylglucosamine;
viii) less than 0.00166% amino acids;
ix) a UV extinction coefficient at 257 nm of less than about 0.23;
x) a UV extinction coefficient at 280 nm of less than 0.19; and
xi) a pH within the range of 7.5-7.7
Other forms of hyaluronic acid and/or its salts may be chosen from other suppliers, for example those described in prior art documents disclosing forms of hyaluronic acid having lower molecular weights between about 150,000 daltons and 750,000 daltons being prepared as for example, 1-2% solutions in sterile water for intravenous administration. In addition, sodium hyaluronate produced and supplied by LifeCore(trademark) Biomedical, Inc. having the following specifications may be suitable (if sterile):
The following references teach hyaluronic acid, sources thereof and processes of the manufacture and recovery thereof.
Canadian Letters Patent 1,205,031 (which refers to U.S. Pat. No. 4,141,973 as prior art) refers to hyaluronic acid fractions having average molecular weights of from 50,000 to 100,000; 250,000 to 350,000; and 500,000 to 730,000 (Protein Standard) and discusses processes of their manufacture.
Where high molecular weight hyaluronic acid (or salts or other forms thereof) is used, it must, prior to use, be diluted to permit administration and ensure no intramuscular coagulation. (Preferably they should be autoclaved to reduce their molecular weight.) Recently, it has been found that large molecular weight hyaluronic acid having a molecular weight exceeding about 1,000,000 daltons self-aggregates and thus, does not interact very well with HA receptors. Thus, the larger molecular weight hyaluronic acid should be avoided (such as Healon(trademark)).
For making the oral dosage forms more pleasant to take taste enhancers or flavours may be added to make the taking more pleasant provided the form of the hyaluronan is not adversely affected (degraded, disassociated or bound up with other materials so as not to be suitable herein). Additionally the dosages may be mixed with a drink liquid to be more enjoyable to take provided the form of hyaluronan is not adversely affected. The dosages may also be taken straight (without their addition to any drink) as there is really no unpleasant flavour.
The invention relates to oral dosages containing forms of hyaluronan and the oral administration thereof to treat or prevent a disease or condition. Thus, the invention can be used for restenosis prevention and other treatments in the same manner that hyaluronan is used. Thus, the invention can be used for the treatments and preventative therapies discussed in the following published and unpublished documents identified below and for the purposes in Canadian Patent Application Serial No. 2,164,260, filed in the Canadian Patent Office on the 1st day of December, 1995 entitled xe2x80x9cTargeting of Dosages of Medicines and Therapeutic Agentsxe2x80x9d, and Canadian Patent Application Serial Number 2,173,037, filed on the 29th day of March, 1996 entitled xe2x80x9cTargeting of Dosages of Medicines and Therapeutic Agents and other Glycosaminoglycans (GAGS)xe2x80x9d, each of which documents is incorporated herein by reference: (with respect to the teachings of each of the documents, the dosages of hyaluronan may be substituted by the oral dosages referred to herein and be used in like manner)
As an example, I have extracted from Application PCT/CA90/00306 (International Publication No. WO 91/04058) the following to illustrate just some of the uses:
(i) at page 17, line 3 to page 18, line 16:
xe2x80x9cApplicants have now discovered that combinations and formulations (for example an injectable formulation) can be provided for administration to a mammal for the treatment of a disease or condition, which combinations or formulations employ or incorporate as the case may be a therapeutically effective non-toxic amount of a medicinal and/or therapeutic agent to treat the disease or condition (for example a free radical scavenger (for example ascorbic acid (Vitamin C)), Vitamin C (for the treatment of mononucleosis), an anti-cancer agent, chemotherapeutic agent, anti-viral agents for example a nonionic surfactant, e.g. nonoxynol9-[nonylphenoxy polyethoxy ethanol] found in Delfen(trademark) contraceptive cream, and anionic surfactants (e.g. cetyl pyridinium chloride) and cationic surfactants (e.g. benzalkonium chloride), non-steroidal anti-inflammatory drugs (NSAID) for example indomethacin, naproxen and (+/xe2x88x92) tromethamine salt of ketorolac (sold under the trademark Toradol(trademark)) and steroidal anti-inflammatory drugs, anti-fungal agent, detoxifying agents (for example for administration rectally in an enema), analgesic, bronchodilator, anti-bacterial agent, antibiotics, drugs for the treatment of vascular ischemia (for example diabetes and Berger""s disease), anti-body monoclonal agent, minoxidil for topical application for hair growth, diuretics (for example furosemide (sold under the trademark Lasix(trademark))), immunosuppressants (for example cyclosporins), lymphokynes (such as interleukinxe2x80x942 and the like), alpha-and-xcex2-interferon and the like) administered with, or carried in, an amount of hyaluronic acid and/or salts thereof (for example the sodium salt) and/or homologues, analogues, derivatives, complexes, esters, fragments, and/or sub units of hyaluronic acid (preferably hyaluronic acid and salts thereof) sufficient to facilitate the agent""s penetration through the tissue (including scar tissue), at the site to be treated through the cell membranes into the individual cells to be treated. When such combinations and formulations are administered to patients suffering from the disease or condition, the disease or condition is unexpectedly improved.
The formulation can be administered among other methods, intravenously, intra arterially, intraperitoneally, intrapleurally, transdermally, on the skin (topically), rectally, orally or by direct injection (for example into a tumor, into an abscess or similar disease focus) or put on a patch to be secured to the skin of the patient. The hyaluronic acid and/or salts thereof and the agent can be administered separately but are administered in sufficient amounts and in an immediate time sequence or interval (preferably concurrently and more preferably simultaneously), preferably at the identical site (e.g. one given intravenously and the other xe2x80x9cpiggy backedxe2x80x9d), to treat the disease or condition.xe2x80x9d
Thus this invention also provides oral dosages comprising effective amounts of the forms of hyaluronan herein described with effective amounts of medicines and/or therapeutic agents and the oral administration of these oral dosages for the treatment and prevention of disease and/or conditions of the human body.